title: Physical limits of cell migration: control by ECM space and nuclear deformation and tuning by proteolysis and traction force.
abstract: Cell migration through 3D tissue depends on a physicochemical balance between cell deformability and physical tissue constraints. Migration rates are further governed by the capacity to degrade ECM by proteolytic enzymes, particularly matrix metalloproteinases (MMPs), and integrin- and actomyosin-mediated mechanocoupling. Yet, how these parameters cooperate when space is confined remains unclear. Using MMP-degradable collagen lattices or nondegradable substrates of varying porosity, we quantitatively identify the limits of cell migration by physical arrest. MMP-independent migration declined as linear function of pore size and with deformation of the nucleus, with arrest reached at 10% of the nuclear cross section (tumor cells, 7 µm²; T cells, 4 µm²; neutrophils, 2 µm²). Residual migration under space restriction strongly depended upon MMP-dependent ECM cleavage by enlarging matrix pore diameters, and integrin- and actomyosin-dependent force generation, which jointly propelled the nucleus. The limits of interstitial cell migration thus depend upon scaffold porosity and deformation of the nucleus, with pericellular collagenolysis and mechanocoupling as modulators.
authors.affiliation: Department of Cell Biology, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, Netherlands. k.wolf@ncmls.ru.nl
authors.forename: Katarina
authors.initials: K
authors.lastname: Wolf
authors.forename: Mariska
authors.initials: M
authors.lastname: Te Lindert
authors.forename: Marina
authors.initials: M
authors.lastname: Krause
authors.forename: Stephanie
authors.initials: S
authors.lastname: Alexander
authors.forename: Joost
authors.initials: J
authors.lastname: Te Riet
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Willis
authors.forename: Robert M
authors.initials: RM
authors.lastname: Hoffman
authors.forename: Carl G
authors.initials: CG
authors.lastname: Figdor
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Weiss
authors.forename: Peter
authors.initials: P
authors.lastname: Friedl
mesh_terms: D000818:Animals; D002417:Cattle; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology*; D003094:Collagen / Q000737:chemistry; D005109:Extracellular Matrix / Q000502:physiology* / Q000648:ultrastructure; D006801:Humans; D020100:Hydrogels / Q000737:chemistry; D016023:Integrins / Q000378:metabolism; D007700:Kinetics; D020782:Matrix Metalloproteinases / Q000378:metabolism / Q000502:physiology; D059748:Proteolysis; D051381:Rats; D013499:Surface Properties
chemical_list: D020100:Hydrogels; D016023:Integrins; D003094:Collagen; D020782:Matrix Metalloproteinases